Current Organic Chemistry - Volume 15, Issue 13, 2011

With the publication of “Fundamentals in Organocatalysis. Past, Present and Future” in Current Organic Chemistry, our fascinating adventure gets to the end. As reflected in recent publications in top journals within the field of Organic Chemistry, the search for novel highly efficient catalytic processes is an active challenge that allows rapid access to complex molecular skeletons. In this respect, during the last decade, metal-free catalysis by using small organic molecules as catalysts has appeared as a useful tool in the field of asymmetric synthesis, being complementary to transition metal catalysis and enzymatic catalysis. Nowadays, great achievements have been reported in this emerging field covering the development of a wide range of catalytic transformations to provide access to the most complex structures, including valuable natural products. The success of this methodology has been increasing day after day attracting the interest of many research groups around the world. In this special issue we wanted to reflect some of the important aims reached in this developing area through the vision of a great group of chemists as experts or emerging but promising researchers in their respective areas of work. We have collected nine appealing contributions regarding this amazing world such as: the work of Prof. Dominguez de Maria and co-workers concerning the Stetter-type reaction: from enzymatic performances to bio-mimetic organocatalytic concepts; the report of Prof. Gasperi and co-workers that provides an overview about the organocatalytic approach to the synthesis of six-membered heterocycles; the work described by Prof. Lattanzi and co-workers which covers the area of noncovalent bifuntional organocatalysis mediated by β-amino alcohols; the contribution of Prof. Merino and coworkers about the organocatalytic activation of imines through hydrogen bond interactions; the review presented by Prof. Ricci and Prof. Bernardi in the field of organocatalytic asymmetric Mannich reactions giving β3-amino acid derivatives; the account reported by Prof. Terada in the field of chiral phosphoric acid catalysts; the review of Prof. Toma and co-workers regarding organocatalytic reactions under unusual conditions; the contribution of Prof. Tsogoeva and co-workers concerning binaphthyl derivatives as Lewis and Brønsted base catalysts; and the review in which I have personally participated together with Prof. Marques-Lopez dedicated to structural aspects of diarylprolinol derivatives. In summary, we think that this special issue might represent a significant contribution in the field of asymmetric organocatalysis, being a reference in this area, and we hope to attract the attention of a broad audience. I do not want to finish without thanking all the authors for their valuable and interesting contributions, which give form to this special issue, and for their efforts and support in this challenging task.

The umpolung bezoin-type and Stetter-type reactions are valuable synthetic strategies to furnish an ample number of important compounds and asymmetric building blocks. Biocatalysis is contributing to this field with several thiamine-dependent lyases, enzymes that are able to catalyze these reactions under mild reaction conditions with high yields and enantioselectivities. Furthermore, recent developments in that field have led to an enzymatic process for the asymmetric Stetter reaction. Likewise, taking Nature as inspiration, several bio-mimetic, organocatalytic approaches have been developed for these syntheses as well. Herein one important strategy comprises the development of “holoenzyme” microenvironments for the organocatalyst, what create hydrophobic conditions that may mimic the role of an enzyme (apoenzyme). That has been achieved by several ways, like set-up of micellar systems, anchoring catalysts to long hydrophobic, aliphatic structures, or by immobilizing organocatalysts to several supports like cyclodextrins, polystyrenes, etc. Another important strategy to mimic enzymatic performances is represented by catalyst design. Herein, starting from seminal work dealing with thiazolium salts - bio-mimetic approach of thiamine, cofactor for enzymes -, impressive developments have been achieved with the establishment of triazolium catalysts as powerful organocatalysts for many asymmetric reactions. The present article will provide an overview from biocatalytic concepts to bio-mimetic possibilities in the field of benzoin-type and Stetter-type reactions.

In the last few years, the new era of organocatalysis opened up an effective and efficient way to high yielding metal free, enantio- and diastereoselective reactions leading to six-membered heterocycles. This review provides an overview of the current achievements in the organocatalytic synthesis of these crucial building blocks. Ranging from hetero-Diels-Alder to cycloadditions, from one step cyclizations to cascade reactions, recent results offer new powerful tools to obtain six membered heterocycles with facile procedures in high yields and stereoselection, often leading to many new stereogenic centres in a single reaction. The total syntheses of natural products having heterocyclic ring formation as crucial stage, are also reported. When available, alternative supported organocatalysts have been examined.

Chiral compounds, bearing closely positioned Bronsted base and Bronsted acid groups, are usefully exploited as bifunctional organocatalysts in a wide array of asymmetric processes. These compounds operate via the generation of a more active nucleophilic species through general base catalysis, whereas the electrophile is activated via hydrogen bonding by the Bronsted acidic group. In this review, we illustrate the achievements appeared in the literature after 2001 up to early 2010, with a focus on reactions mediated by organocatalysts bearing the β-amino alcohol core as their catalitically active site. 1,2-Additions, ring-closure reactions, conjugate additions, α- functionalization of carbonyl compounds are efficiently accomplished by β-amino alcohols as catalysts. Most of the processes described are promoted by cinchona alkaloids, whereas some examples include the use of L-proline derivatives such as α,α-diaryl prolinols. The ready availability of β-amino alcohols from the chiral pool, makes them an appealing class of versatile promoters to exploit in modern organic synthesis.

Activation of imines by hydrogen bonding is a very powerful way of promoting the synthesis of a variety of nitrogencontaining compounds of interest. Such a useful approach typically involves mild reaction conditions, simple experimental operations and metal-free reagents. The present review focuses on the recent development of new organocatalytic methods involving imines and related compounds as substrates in which activation through hydrogen bonding is performed. The different modes of activation are thoroughly illustrated with special emphasis on mechanistic aspects of the reactions and how activation is actually produced.

Organocatalytic, asymmetric Mannich reactions giving β3-amino acid derivatives have been reviewed. The Mannich-type addition of an acetate anion to an imine represents in fact one of the most direct routes to this particular class of β-amino acids. However, due to the low acidity of simple acetates, synthetic equivalents of acetate anions had to be used. These include preformed enolates (silylketeneacetals), carbonylic compounds with improved reactivity (acetophenones and their enamines/enamides), acetates equipped with a removable group enhancing their acidity (malonates, nitroacetates, sulfonylacetates, diazoacetates), acetates able to undergo decarboxylative enolate formation (malonic acid half thioesters), and finally acetaldehyde. Each of these equivalents was combined with the requisite organocatalytic strategy, giving very powerful and effective methods for the preparation of β3-amino acid precursors. The simple and straightforward manipulations, used to convert these products into the target β3-amino acid compounds, are also described.

Chiral phosphoric acids derived from axially chiral biaryls and analogous chiral Bronsted acids have emerged as an attractive and widely applicable class of enantioselective organocatalysts for a variety of organic transformations. In this account article, we review our recent achievements and related works in the development of enantioselective carbon-carbon bond forming reactions using these axially chiral phosphoric acids and their analogues as chiral Bronsted acid catalysts. The contents are arranged according to the type of (pro)electrophiles, including imines, hemiaminal ethers, carbonyl compounds, and electron-rich double bonds, followed by specific reaction types. Further application to phosphoric acid/metal complex-combined catalytic systems is also highlighted.

Organocatalyzed reactions can often be advantageously performed in non-traditional reaction media. Use of ionic liquids, water or brine often leads to improved yields and selectivities of organocatalytic transformations. In terms of energy source, organocatalyzed reactions can be significantly accelerated by microwave irradiation, ultrasound or high pressure. Reactions without solvent and performed in ball mills are also reviewed.

Lewis and Bronsted base catalysis are rapidly growing areas in organocatalysis. Numerous binaphthyl-derived chiral base catalysts has been developed over the last years. Recent progress in the chiral Lewis and Bronsted base catalysis has been reviewed with a focus being placed on mono-functional catalysts, including primary and secondary diamines, guanidines, phosphines and phosphineoxides; bi- and multifunctional catalysts, covering secondary and/or tertiary amine and phosphine derivatives assisted with urea/thiourea hydrogen bond donors or Lewis/ Bronsted acids.

The synthesis of complex active molecules has afforded the search for new methods and new processes in organic synthesis. In this context, organic metal free catalysis has appeared as a powerful tool being complementary to metal catalysis in the field of asymmetric synthesis. The success of this methodology has been increasing in the last decade and the research for new organocatalytic systems as well as new applications has attracted the interest of many research groups. Among all organocatalysts, diarylprolinol derivatives have emerged as powerful scaffolds for asymmetric catalysis, proof of that is the huge number of publications reported using this kind of structure as catalysts. However, only in a few cases, different aspects of the catalysts structures and additional additives have been largely studied and a plausible explanation has been given. In this sense, this review treats to illustrate these important and scarce examples and to give a very general vision relating to the application of diarylprolinol derivatives in organocatalytic transformations from another point of view: structural aspects. The influence of catalyst structure, electronic effects, and the use of additives will be the aim of discussion and comment in this work.